Powdered ointment base of methyl cellulose and sorbitol



Patented Oct. 11, 1949 POWDERED OINTMENT BASE OF METHYL CELLULOSE ANDSORBITOL Albert M. Mattocks, Jr., and Wilbur A. Lazler,

Birmingham, Ala., assignors to Southern Research Institute, Birmingham,Ala., a corporation of Alabama No Drawing. Application August 20, 1946,

Serial No. 691,867

1 Claim. 1

This invention relates to new therapeutic preparations and moreparticularly refers to dry, stable therapeutic powders capable onaddition of Water of rapid transformation into gelatinous ointments orointment vehicles.

It is well known in the pharmaceutical field that the formulation,storage, and dispensing of drugs in water-miscible solid vehicles haspresented such extraordinary difficulties that hydrophilic ointmentshave been very little used. Wet

. jellies such as starch paste and colloidal suspensions of the solubleproteins and vegetable gums not only are bulky and tend to leak as aresult of syneresis, but often give rise to various forms of microbialdeterioration. Moreover, they tend to dry out, thus defeating thepurpose for which they were compounded. Once dried, it is well knownthat such ointment bases are not easily rehydrated to give jellieshaving the proper texture.

Notwithstanding the foregoing difficulties, ointment bases ofhydrophilic character have been demonstrated repeatedly to be useful inreleasing medicaments for absorption through the skin, when applied tolocal areas of the body. For example, extensive experiments in the useof sulfa drugs have indicated the superiority of waterdispersiblepreparations for the application ofthese compounds. In the same manner,clinical tests have demonstrated the value of hydrophilic ointments as ameans of bringing powerful antibiotics into contact with surfaces of thebody. A special problem in this connection is removal of necrotic tissuefrom the site of burned tissue. The removal of such tissue is importantto avoid infection and permit granulation of new tissue which protectsand heals the wound. In the past, mechanical debridement of burns byscrubbing or surgery was common, but it caused considerable pain andincreased the danger from shock. In addition, it has been found todamage or remove residual islands of epithelial cells capable ofregenerating new tissue.

In an endeavor to avoid the disadvantages of the customary mechanicaldebridement treatment for burns, attempts have been made to removenecrotis tissue therefrom by chemical means. G. Connor and S. C. Harvey(Ann. Surgery 120, 362 (1944)) found that jells containing organic acidssuch as pyruvic acid or succinic acids cause removal of slough in asingle tough pellicle, leaving a clean granulating surface. Connor andHarvey used cornstarch paste containing pyruvic acid in a sufficientconcentration to yield a jellyhaving a pH of 1.9. Serious objections,however,

were encountered in the general use of such an ointment since theprepared paste was biologically unstable and it was troublesome toprepare it in fresh condition as needed.

From the foregoing it is evident that despite the great need forhydrophilic ointments, the difficulty of storing them or preparing themwhen needed has been such that these ointments have not received thewidespread use which their effectiveness warrants. This is true not onlyfor ointments which are particularly adapted for the treatment of burnsbut also for hydrophilic ointments generally as vehicles for theapplication of medicaments to the skin.

It is an object of this invention to produce an entirely new class ofeasily wettable therapeutic ointment powders. It is a further object toproduce ointments in powder form that are compact, biologically andchemically stable, and easily and quickly convertible on addition ofwater into therapeutically active jellies suitable for the treatment ofwounds. A still further object is to produce an ointment vehicle inpowder form having the aforesaid properties, to which may be addedwhatever medicament is desired at the time of use. Additional objectswill become apparent from aconsideration of the following descriptionand claims.

These objects are attained in accordance with the present invention bymixing a cellulose ether with a wetting agent and finely comminuting themixture either before or after incorporation therein of the desiredmedicament. In a more restricted sense this invention is concernedwithdry, stable therapeutic powders which speedily dissolve in water toform jellies capable of producing an adherent coating over woundscomprising a finely comminuted cellulose ether throughout which isuniformly incorporated a wetting agent, and if desired, a medicament. Inits preferred embodiment the cellulose ether is methyl cellulose and thewetting agent is sorbitol.

Ethers of cellulose have been found to be surprisingly satisfactoryswelling agents for the powders of this invention since they aresubstantially unattacked by microorganisms, remain stable when storedunder widely varying conditions, and form excellent jellies whendissolved in water. Unfortunately, cellulose ethers are notoriously slowin dissolving in water, as a result of which their application fortherapeutic purposes has been seriously retarded. For instance, when achemist wishes to make an aqueous solution of methyl cellulose heordinarily soaks it in cold water in a refrigerator overnight. If oneadds sorbitol or some other wetting agent to the water the time requiredto dissolve the cellulose ether is not substantially lowered.

We have found that by mixing sorbitol or other suitable wetting agentwith the cellulose ether and finely comminuting the mixture in a hammermill or other efficient grinding device, a dry, stable powder isobtained which dissolves in water almost instantaneously, in contrastwith the inordinate periods formerly considered to be essential. Inaccordance with this invention, the powdered cellulose ether may bemixed in a dry form with a wetting agent to which has been added, ifdesired, a medicament, and the mixture thereafter finely comminuted bypassing through a hammer mill or similar device. However, optimumresults are obtained if the cellulose ether is first added to an aqueoussolution of the wetting agent (with or without medicament) and themixture stirred for a prolonged period until a homogeneous ointment isformed. Thereafter this ointment is dehydrated in thin layers, such asby spreading the mixture on sheets of glass in layers about one-halfcentimeter thick and drying for 24 hours in an oven at about 75 C.

The dehydrated sheets thus produced are then finely comminuted in apulverizing mill. The resulting powder has the surprising property ofcompletely redissolving in water in approximately 1 minute, so that itcan be converted to an ointment whenever needed, and if desiredmedicament may be added at the time of use.

By the unique methods referred to above we have succeeded for the firsttime in preparing dry, easily wettable, biologically stable, solidtherapeutic ointment bases wherein the gelling agent is a celluloseether. These powders may have the medicament incorporated therewithbefore comminution in the manner referred to previously. or if=anall-purpose ointment vehicle is desired the medicament may be omitted,to be added at the time of use. Preparation of these powders with methylcellulose, hydroxyethyl cellulose or other cellulose ethers as thegelling agents, imparts specific desirable characteristics to theresulting ointments. These agents have good body and cling toundersurfaces without tendency to flow. They are free from irritationand are inert towards microbial attack. Their viscosities may be variedwithin a wide range by varying the amount of wetting agent and theamount of water added thereto.

While methyl cellulose is a preferred cellulose ether, it has been foundthat ethyl cellulose, propyl cellulose, and related ethers may beemployed. Likewise. substituted cellulose ethers such as hydroxyethylcellulose and cellulose glycollic acid may be used. These ce luloseethers may be employed alone or in admixture with one another, and it iscontemplated that other gelling agents may be added thereto although foroptimum results it is preferred to employ only cellulose ethers for thispurpose.

sorbitol is the preferred wetting agent. However. other wetting agentsmay be employed and in particular those wetting agents commonly known asnon-polar or non-ionic wetting agents. The non-ionic wetting agents mavbe illustrated by the well known polyhydric alcohols and their ethersand e ters. Since sorbitol is a solid, nontoxic material it is ideallysuited for employment as a wetting agent in the compounds of thisinvention.

The grinding operation which is essential to finely comminute thecellulose ether and wetting agent may be carried out in avariety ofstandard mills such as the micropulverizer, the ball mill,

the hammer mill, the burr mill, or the micronizer.

This invention may be more readily understood by a consideration of thefollowing illustrative examples wherein the quantities, unless otherwiseindicated, are stated in parts by weight.

Example 1 One hundred parts of methyl cellulose and 20 parts of anaqueous solution of sorbitol was thoroughly mixed and passed severaltimes through a hammer mill. The product was a fine white powder.Whereas the original methyl cellulose dissolved very slowly, it wasfound that the fine powder produced as aforesaid could be easily wettedin less than a minute.

Example 2 One hundred parts of methyl cellulose was incorporated with 20parts of Xynomine (wetting agent) and 9.5 parts of pyruvic acid. Themixture was finely ground in a hammer mill until the whole mass wouldeasily pass through a fine screen. The resulting fine white powder had afluffy appearance and swelled rapidly in eight parts of water to give a.sticky semitransparent paste of a proper consistency for application asan ointment. The acidityof the aqueous ointment measured pH 1.87. Theointment was found to be very effective when applied as a dressing forthe debridement of thermal or chemical burns.

Example 3 One hundred parts of methyl cellulose, 20 parts of 85%sorbitol syrup, and 12.3 parts of pyruvic acid was thoroughly mixed andpassed through a pulverizing mill. The resulting fine powder wetted withwater in 2 minutes to give a clear jelly, having a pH of 2.28.Similarly, another acid debridement composition was prepared bysubstituting 16.7 parts of phosphoric acid for the pvruvic acid usedabove. The pH of this composition was 1.6.

Example 4 One hundred parts of high viscosity hydroxyethyl cellulose wasformulated with 8.9 parts of pyruvic acid and 25 parts of Arlacel C(wetting agent). After thorough grinding in a pulverizing mill themixture dissolved to a clear jelly in a matter of a few minutes ascompared with several hours for the untreated hydroxylethyl cellulose.

Example 5 Example 6 Fifty parts of methyl cellulose. ten parts ofsorbitol, and six hundred and sixty-seven parts of water were mixed witha mechanical stirring device until a homogenous gel was formed. Threeand six-tenths parts of local anesthetic. procaine-hydrochloride, wasadded and mixed thoroughl with the gel. After drying in thin layers at75 C. for twenty-four hours, the mass was finely pulverized. Theresultant dry powder speedily wetted with water to form an ointment wtihlocal anesthetic properties.

Example 7 One hundred and fifty parts of methyl cellulose, thirty partsof sorbitol, and two thousand parts of water were mixed with amechanical stirring device until a homogenous gel was formed. Ten andnine-tenths parts of ephedrine hydrochloride dissolved in three hundredparts of water was added and mixed thoroughly with the gel. The mass wasdried in thin layers at 75 C. for twenty-four hours and then finelypulverized. On wetting with water, the powder dissolved rap idly to forma clear ointment with vasoconstrictor properties.

Example 8 One hundred and fifty parts of methyl cellulose, thirty partsof sorbitol, and two thousand parts of water were mixed in a powerdriven mixer until a homogenous gel was formed. Two hundred and eighteenparts of finely powdered salicylic acid and one hundred and nine partsof finely powdered benzoic acid were added and mixed thoroughly with thegel. The mass was dried in a stream of warm air 100 C. until a dry filmwas obtained and then finely pulverized. The resultant dry powder waseasily wettable with water to form an ointment useful for treatment ofskin diseases.

Example 9 One hundred parts of methyl cellulose, twenty parts ofsorbitol, one thousand three hundred and thirty-three parts of waterwere mixed with a mechanical stirring device until a homogenous gel wasformed. Seventy-two parts of finely powdered yellow mercuric oxide wereadded and mixed thoroughly with the gel. The mass was dried in thinlayers at 75 C. for twenty-four hours and then finely pulverized.

Example 10 One hundred and fifty parts of methyl cellulose, thirty partsof sorbitol, and two thousand parts of water were mixed with amechanical stirring device until a homogenous gel was formed. Twenty-oneand eight-tenths parts of lactic acid was added and mixed thoroughlywith the gel. The mass was dried in thin layers at 75- C. fortwenty-four hours and then finely pulverized. The resultant dry powderspeedily wetted with water to form an ointment with contraceptiveproperties.

Example 11 One hundred and fifty parts of methyl cellulose, thirty partsof sorbitol, and two thousand parts of water were thoroughl mixed over aperiod of time suflicient to swell and uniformly incorporated them intoa homogenous gel. One hundred and nine parts of argyrol dissolved infive hundred parts of water were added and mixed thoroughly with thegel. The mass was dried and then finely pulverized. The resultant drypowder readily wetted with water to form an ointment with antisepticproperties.

Example 12 One hundred and fifty parts of methyl cellulose, thirty partsof sorbitol, and two thousand parts of water were mixed with amechanical stirring device until a homogenous gel was formed. A solutionof one hundred and nine parts of mercurochrome in five hundred parts ofwater was added and mixed thoroughly with the gel. The mass was dried ina'stream of warm air for twenty-four hours'and then finely pulverized.The resultant dry powder speedily wetted with water to form an ointmentwith antiseptic properties.

Example 13 One'hundred and fifty parts of methyl cellulose, thirty partsof sorbitol, and two thousand parts of distilled water were mixed with amechanical stirring device until a homogenous gel was formed. A solutionof ten and nine-tenths parts of silver nitrate dissolved in one thousandparts of water was added and mixed thoroughly with the gel. The mass wasdried in thin layers at 75 C. for twenty-four hours and then finelypulverized. The resultant dry powder speedily wetted with water to forman ointment with antiseptic properties.

Example 14 To one hundred parts of finely powdered hydroxyethylcellulose (high viscosity) was added with thorough mixing a solution oftwenty-five parts of Arlacel C (wetting agent) and four and eighty-fivehundredths parts of pyruvic acid in five hundred parts of acetone. Theacetone was then evaporated from the mixture, and the residual mass wasground to a fine powder in a hammer mill. One part of this powder wettedreadily with three parts of water to yield an ointment of pH 2.50suitable for use in the debridement of burns.

Example 15 One hundred and fifty parts of methyl cellulose, thirty partsof sorbitol, and two thousand parts of water were mixed with amechanical stirring device until a homogenous gel was formed. Onehundred and nine parts of sulfathiazole, finely powdered, was added andmixed thoroughly with the gel. The mass was dried in thin layers at 75C. for twenty-four hours and then finely pulverized. The resultant drypowder readily wetted with water to form an ointment useful fortreatment of infections. A similar ointment was prepared in a likemanner from methyl cellulose, sorbitol, and sulfadiazine.

Example 16 One hundred and fifty parts of methyl cellulose,

thirty parts of sorbitol, and two thousand parts of water were mixedwith a mechanical stirring device until a homogenous gel was formed. Onehundred and nine parts of sulfanilamide, finely powdered, was added andmixed thoroughly with the gel. The mass was dried in thin layers at 75C. for twenty-four hours and then finely pulverized. The resultant drypowder readily wetted with water to form an ointment useful fortreatment of infections.

Example 17 without departing from the scopeof this invention. Asmentioned previously, other cellulose ethers, as well as other wettingagents, may be employed in the above examples in lieu of methylcellulose and sorbitol. Likewise, mixtures of cellulose ethers orwetting agents may be used. The amount of cellulose ether is of coursesubstantially larger than the amount of wetting agent. As a generalrule, for 100 parts by weight of cellulose ether approximately to 40parts by weight of wetting agent is sufficient.

When the medicament is to be added to the ointment bale at the time ofpreparation thereof any desired concentration necessary for theparticular purpose to which the ointment is to be applied may be used.As a general rule, the medicament will vary from less than 1% to as highas 10 or by weight of the ointment base, although larger amounts may beused if desired.

A wide variety of medicaments or mixtures thereof may be employed. Wherethe medicament is to be added to the ointment base when the latter isprepared it is of course advisable that it be stable on storage. If amedicament is unstable under the conditions of storage then it should beadded to the ointment vehicle at the time the latter is dissolved inwater, just prior to application to the wound.

A representative group of medicaments which may be incorporated in theointment bases of the present invention includes mercurochrome,sulfapyridine, sulfathiazole, sulfadiazine, bichloride of mercury,silver nitrate, argyrol, boric acid, phosphoric acid, pyruvic acid;anesthetic agents such as procaine and butycaine; vasoconstrictors suchas epinephrine and cocaine; antiseptics such as salicylic and benzoicacids and derivatives, zinc and mercury oxides, calamine, phenol, andcresol; oxidizing agents such as the more stable peroxides andchloramines; counter irritants such as mustard oil, menthol, eucalyptol,and camphor; coal tar products commonly used as parasiticides and fordermatitis; spermacides and contraceptive agents such as thymol and itsderivatives, hexylresorcinol and hydroxyquinolines; colloidal silverproteins and protamines for treatment of infectious diseases; hormonessuch as testosterone and estrin for topical application, etc.

By means of the present invention an important class of new hydrophilicointments and ointment bases has been made available for therapeuticpurposes. These ointments and ointment bases are free from the manydisadvantages which have heretofore precluded the use of watermiscible,solid vehicles in the pharmaceutical industry. They are dry, stablepowders which may be stored for long periods, but which dissolve readilyin water when needed to produce an ointment 0r ointment vehicle of thedesired characteristics.

As many apparently widely different embodiments of this invention may bemade without departing from the spirit and scope hereof, it is to beunderstood that the invention is not limited to the specific.embodiments hereof except as defined in the appended claim.

We claim: v

A biologically and chemically stable ointment base in the form of a drypowder comprisin a finely comminuted mixture of methyl cellulose andsorbitol containing from 10 to 40 parts by weight of sorbitol for eachparts by weight of methyl cellulose, said powder being readily solublein water in approximately one minute.

ALBERT M. MATTOCKS, JR. WILBUR A. LAZIER.

REFERENCES CITED The following references are of file of this patent:

UNITED STATES PATENTS record in the Number Name Date 2,288,200 MeyerJune 30, 1942 2,321,270 Bacon et a1. June 8. 1943 FOREIGN PATENTS NumberCountry Date 156,725 Great Britain July 7, 1922 514,354 Great BritainJan. 25, 1938 739,630 Germany Sept. 30, 1943 OTHER REFERENCES Section1943, page

